Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway
Research highlights
► Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells ► Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway ► Curcumin induces A549/DDP cell apoptosis by downregulating miR-186∗ ► miR-186∗ may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin
Introduction
Lung cancer is the most common malignant tumor worldwide, and it is one of the leading causes of human cancer-related deaths [1]. Following the use of cisplatin chemotherapy, many changes have been associated with the multidrug-resistance phenotype of tumor cells [2], [3]. Cancer chemotherapy is limited by the development of drug resistance by cancer cells and the adverse effects of anti-tumor drugs. The search for novel anti-tumor agents that circumvent these limitations has turned to natural plants [4].
Curcuma longa L. is a plant that belongs to the Zingiberaceae family. Curcumin, which is extracted from the rhizomes of C. longa L. is the major component of this plant [5]. Diverse pharmacological effects induced by curcumin have been reported, including anti-inflammatory, antioxidant, and anti-tumor activities [6], [7], [8]. There is a wealth of experimental evidence suggesting that multiple mechanisms of action are likely responsible for the various pharmacologic effects of curcumin on cancer-related signaling molecules [9], [10]. These include modulation of Jak/STAT, NF-κB, jun, extracellular signal regulated kinase and other key molecules involved in tumorigenesis. Recent results suggest that curcumin can inhibit the proliferation of pancreatic cancer cells through the regulation of specific miRNAs [11]. These emerging results clearly suggest that specific targeting of miRNAs by natural agents may open new avenues for the complete eradication of tumors by killing the drug-resistant cells and improve survival outcomes in patients diagnosed with malignancies [12].
The aim of this study was to probe the anti-cancer effects of curcumin on A549/DDP multidrug-resistant human lung adenocarcinoma cells. In addition, the related miRNA mechanism of apoptosis was also analyzed.
Section snippets
Cell culture
The human lung adenocarcinoma cell line A549 and the multidrug-resistant human lung adenocarcinoma cell line A549/DDP (obtained from the Academy of Military Medical Science, Beijing, China) were cultured in our laboratory. To maintain drug resistance, A549/DDP cells were cultured with 6 μmol/L DDP and were further cultured in DDP-free RPMI 1640 medium two days before starting the experiment.
MTT assay
The growth inhibitory effect of curcumin (Sigma, St. Louis, USA) on A549 and A549/DDP cells was assessed
Results
Curcumin could significantly inhibit A549 and A549/DDP cells growth in MTT assays, and the inhibition ratio was markedly increased in a dose- and time-dependent manner (Fig. 1A). The IC50 of curcumin at 48 h were 16.28 ± 1.4 μmol/L for A549 cells and 18.06 ± 1.9 μmol/L for A549/DDP cells (Fig. 1B), which were not significantly different (P ⩾ 0.05). These data demonstrate that A549/DDP cells are still sensitive to curcumin.
Discussion
The leading cause of chemotherapy failure is tumor resistance. Therefore, the search for new drugs that can evade drug resistance and adverse effects is very important in the clinic [17]. Since the Indian researcher Kuttan [5] reported that curcuma and curcumin may have anti-tumor effects, a large amount of research has proven that curcumin can induce apoptosis in many types of cancer cells [18], [19] through inhibition of NF-κB, survivin/BIRC5, and bcl2 [20], [21]. Although there is evidence
Acknowledgments
This work was supported by a grant sponsor: National Natural Science Foundation of China; Grant number: 30572359.
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The first three authors contributed equally to this work.